Laminin-521 is a Novel Target of Autoantibodies Associated with Lung Hemorrhage in Anti-GBM Disease

Abstract

Significance Statement Antiglomerular basement membrane (GBM) disease clinically presents as rapidly progressive GN, often accompanied by pulmonary hemorrhage. The autoantibodies that mediate the disease typically recognize cryptic epitopes within α345(IV) collagen in the glomerular and alveolar basement membranes. Laminin-521 is another major autoantigen that autoantibodies in anti-GBM disease target. These autoantibodies were detected in 51.5% of patients with both kidney and lung involvement of anti-GBM disease, compared with 23.5% of patients with isolated kidney disease. Seropositivity for antilaminin autoantibodies was significantly associated with lung hemorrhage, hemoptysis, and smoking. Antilaminin autoantibodies may contribute to lung injury in anti-GBM disease by increasing the amount of IgG bound to the alveolar basement membrane. Background Antiglomerular basement membrane (anti-GBM) disease is characterized by GN and often pulmonary hemorrhage, mediated by autoantibodies that typically recognize cryptic epitopes within α345(IV) collagen—a major component of the glomerular and alveolar basement membranes. Laminin-521 is another major GBM component and a proven target of pathogenic antibodies mediating GN in animal models. Whether laminin-521 is a target of autoimmunity in human anti-GBM disease is not yet known. Methods A retrospective study of circulating autoantibodies from 101 patients with anti-GBM/Goodpasture’s disease and 85 controls used a solid-phase immunoassay to measure IgG binding to human recombinant laminin-521 with native-like structure and activity. Results Circulating IgG autoantibodies binding to laminin-521 were found in about one third of patients with anti-GBM antibody GN, but were not detected in healthy controls or in patients with other glomerular diseases. Autoreactivity toward laminin-521 was significantly more common in patients with anti-GBM GN and lung hemorrhage, compared with those with kidney-limited disease (51.5% versus 23.5%, P =0.005). Antilaminin-521 autoantibodies were predominantly of IgG1 and IgG4 subclasses and significantly associated with lung hemorrhage ( P =0.005), hemoptysis ( P =0.008), and smoking ( P =0.01), although not with proteinuria or serum creatinine at diagnosis. Conclusions Besides α345(IV) collagen, laminin-521 is another major autoantigen targeted in anti-GBM disease. Autoantibodies to laminin-521 may have the potential to promote lung injury in anti-GBM disease by increasing the total amount of IgG bound to the alveolar basement membranes.

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